Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.3 · PDF-Seite 6

HOS-146349 · Präparat HOS-099502

Hypersensitivity to the active substance, peanut or soya, or to any of the excipients listed in section 6.1.

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Gegenanzeigen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.3 · PDF-Seite 6

HOS-146350 · Präparat HOS-099502

Doxorubicin pegylated liposomal must not be used to treat AIDS-KS that may be treated effectively with local therapy or systemic alfa-interferon.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): doxorubicin (HOS-084538)

Wechselwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.5 · PDF-Seite 9

HOS-146351 · Präparat HOS-099502

No formal medicinal product interaction studies have been performed with doxorubicin pegylated liposomal, although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynaecological malignancies. Exercise caution in the concomitant use of medicinal products known to interact with standard doxorubicin hydrochloride. Doxorubicin pegylated liposomal, like other doxorubicin hydrochloride preparations, may potentiate the toxicity of other anti-cancer therapies. During clinical trials in patients with solid tumours (including breast and ovarian cancer) who have received concomitant cyclophosphamide or taxanes, no new additive toxicities were noted. In patients with AIDS, exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with standard doxorubicin hydrochloride. Caution must be exercised when giving any other cytotoxic agents, especially myelotoxic agents, at the same time.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): doxorubicin hydrochloride (HOS-085564) mercaptopurine (HOS-085568) cyclophosphamide (HOS-084539) doxorubicin (HOS-084538)

Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-146355 · Präparat HOS-099502

Summary of the safety profile The most frequent adverse reactions (≥ 20%) were neutropaenia, nausea, leukopaenia, anaemia, and fatigue.

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-146356 · Präparat HOS-099502

Severe adverse reactions (Grade 3/4 adverse reactions occurring in ≥ 2% of patients) were neutropaenia, PPE, leukopaenia, lymphopaenia, anaemia, thrombocytopaenia, stomatitis, fatigue, diarrhoea, vomiting, nausea, pyrexia, dyspnoea, and pneumonia. Less frequently reported severe adverse reactions included Pneumocystis jirovecii pneumonia, abdominal pain, cytomegalovirus infection including cytomegalovirus chorioretinitis, asthenia, cardiac arrest, cardiac failure, cardiac failure congestive, pulmonary embolism, thrombophlebitis, venous thrombosis, anaphylactic reaction, anaphylactoid reaction, toxic epidermal necrolysis, and Stevens-Johnson syndrome.

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-146357 · Präparat HOS-099502

Tabulated list of adverse reactions Table 5 summarises the adverse drug reactions that occurred in patients receiving doxorubicin pegylated liposomal in 4,231 patients for the treatment of breast cancer, ovarian cancer, multiple myeloma, and AIDS-related KS. Post-marketing adverse reactions are also included, as indicated by “b”. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-146358 · Präparat HOS-099502

Table 5: Adverse reactions in patients treated with doxorubicin pegylated liposomal

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-146359 · Präparat HOS-099502

System Frequency all grades Adverse drug reaction Organ Class Infections Common Sepsis and Pneumonia infestations Pneumocystis jirovecii pneumonia Cytomegalovirus infection including cytomegalovirus chorioretinitis Mycobacterium avium complex infection Candidiasis Herpes zoster Urinary tract infection Infection Upper respiratory tract infection Oral candidiasis Folliculitis Pharyngitis Nasopharyngitis Uncommon Herpes simplex Fungal infection Rare Opportunistic infection (including Aspergillus, Histoplasma, Isospora, Legionella, Microsporidium, Salmonella, Staphylococcus, Toxoplasma, Tuberculosis)a Not known Acute myeloid leukaemiab

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 10–12

HOS-146360 · Präparat HOS-099502

10 Neoplasms Myelodysplastic syndromeb benign, Oral neoplasmb malignant and unspecified (including cysts and polyps) Blood and Very common Leukopaenia lymphatic Neutropaenia system disorders Lymphopaenia Anaemia (including hypochromic) Common Thrombocytopaenia Febrile neutropaenia Uncommon Pancytopaenia Thrombocytosis Rare Bone marrow failure Immune Uncommon Hypersensitivity system Anaphylactic reaction disorders Rare Anaphylactoid reaction Metabolism Very common Decreased appetite and nutrition Common Cachexia disorders Dehydration Hypokalaemia Hyponatraemia Hypocalcaemia Uncommon Hyperkalaemia Hypomagnesaemia Psychiatri Common Confusional state c Anxiety disorders Depression Insomnia Nervous Common Neuropathy peripheral system Peripheral sensory neuropathy disorders Neuralgia Paraesthesia Hypoaesthesia Dysgeusia Headache Lethargy Dizziness Uncommon Polyneuropathy Convulsion Syncope Dysaesthesia Somnolence Eye disorders Common Conjunctivitis Uncommon Vision blurred Lacrimation increased Rare Retinitis Cardiac Common Tachycardia disorders Uncommon Palpitations a Cardiac arrest Cardiac failure Cardiac failure congestive Cardiomyopathy 11  Cardiotoxicity Rare Ventricular arrhythmia Bundle branch block right Conduction disorder Atrioventricular block Cyanosis Vascula Common Hypertension r Hypotension disorder s

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 12–13

HOS-146361 · Präparat HOS-099502

12  Flushing Uncommon Pulmonary embolism Infusion site necrosis (including soft tissue necrosis and skin necrosis) Phlebitis Orthostatic hypotension Rare Thrombophlebitis Venous thrombosis Vasodilatation Respiratory, Common Dyspnoea thoracic and Dyspnoea exertional mediastinal Epistaxis disorders Cough Uncommon Asthma Chest discomfort Rare Throat tightness Not Known Interstitial lung disease Gastrointestinal Very common Stomatitis disorders Nausea Vomiting Diarrhoea Constipation Common Gastritis Aphthous stomatitis Mouth ulceration Dyspepsia Dysphagia Oesophagitis Abdominal pain Abdominal pain upper Oral pain Dry mouth Uncommon Flatulence Gingivitis Rare Glossitis Lip ulceration Skin and Very common Palmar plantar erythrodysaesthesia syndromea subcutaneous Rash (including erythematous, maculo-papular, and tissue disorders papular) Alopecia Common Skin exfoliation Blister Dry skin Erythema Pruritus Hyperhidrosis Skin hyperpigmentation Uncommon Dermatitis Dermatitis exfoliative Acne Skin ulcer Dermatitis allergic

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 13–14

HOS-146362 · Präparat HOS-099502

1  Urticaria Skin discolouration Petechiae Pigmentation disorder Nail disorder Rare Toxic epidermal necrolysis Erythema multiforme Dermatitis bullous Lichenoid keratosis Not known Stevens-Johnson syndromeb Musculoskeletal Very common Musculoskeletal pain (including musculoskeletal chest and connective pain, back pain, pain in extremity) tissue disorders Common Muscle spasms Myalgia Arthralgia Bone pain Uncommon Muscular weakness Renal and Common Dysuria urinary disorders Not Known Renal-limited thrombotic microangiopathy Reproductive Uncommon Breast pain disorders Rare Vaginal infection Scrotal erythema General Very common Pyrexia disorders and Fatigue administration Common Infusion-related reaction site conditions Pain Chest pain Influenza-like illness Chills Mucosal inflammation Asthenia Malaise Oedema Oedema peripheral Uncommon Administration site extravasation Injection site reaction Face oedema Hyperthermia Rare Mucous membrane disorder Investigations Common Weight decreased Uncommon Ejection fraction decreased Rare Liver function test abnormal (including Blood bilirubin increased, Alanine aminotransferase increased and Aspartate aminotransferase increased)

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 14

HOS-146363 · Präparat HOS-099502

Blood creatinine increased Injury, poisoning Uncommon Radiation recall phenomenona and procedural complications a See Description of selected adverse reactions b Post-marketing adverse reaction

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 14–15

HOS-146364 · Präparat HOS-099502

2 Description of selected adverse reactions

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-146365 · Präparat HOS-099502

Palmar plantar erythrodysaesthesia The most common undesirable effect reported in breast/ovarian clinical trials was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 41.3% and 51.1% in the ovarian and breast clinical trials, respectively. These effects were mostly mild, with severe (grade 3) cases reported in 16.3% and 19.6% of patients. The reported incidence of life-threatening (grade 4) cases was < 1%. PPE infrequently resulted in permanent treatment discontinuation (1.9% and 10.8%). PPE was reported in 16% of multiple myeloma patients treated with doxorubicin pegylated liposomal plus bortezomib combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE was reported. The rate of PPE was substantially lower in the AIDS-KS population (1.3% all grade, 0.4% grade 3 PPE, no grade 4 PPE). See section 4.4.

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-146366 · Präparat HOS-099502

Opportunistic infections Respiratory undesirable effects commonly occurred in clinical studies of doxorubicin pegylated liposomal and may be related to opportunistic infections (OI’s) in the AIDS population. Opportunistic infections are observed in KS patients after administration with doxorubicin pegylated liposomal, and are frequently observed in patients with HIV induced immunodeficiency. The most frequently observed OI’s in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis jirovecii pneumonia, and mycobacterium avium complex.

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-146367 · Präparat HOS-099502

Cardiac toxicity An increased incidence of congestive heart failure is associated with doxorubicin therapy at cumulative lifetime doses > 450 mg/m2 or at lower doses for patientswith cardiac risk factors. Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of doxorubicin pegylated liposomal greater than 460 mg/m2 indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of doxorubicin pegylated liposomal for AIDS-KS patients is 20 mg/m2 every two-to-three weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (> 400 mg/m2) would require more than 20 courses of doxorubicin pegylated liposomal therapy over 40 to 60 weeks.

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-146368 · Präparat HOS-099502

In addition, endomyocardial biopsies were performed in 8 solid tumour patients with cumulative anthracycline doses of 509 mg/m2-1,680 mg/m2. The range of Billingham cardiotoxicity scores was grades 0-1.5. These grading scores are consistent with no or mild cardiac toxicity.

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-146369 · Präparat HOS-099502

In the pivotal phase III trial versus doxorubicin, 58/509 (11.4%) randomised subjects (10 treated with doxorubicin pegylated liposomal at a dose of 50 mg/m2/every 4 weeks versus 48 treated with doxorubicin at a dose of 60 mg/m2/every 3 weeks) met the protocol-defined criteria for cardiac toxicity during treatment and/or follow-up. Cardiac toxicity was defined as a decrease of 20 points or greater from baseline if the resting LVEF remained in the normal range or a decrease of 10 points or greater if the LVEF became abnormal (less than the lower limit for normal). None of the 10 doxorubicin pegylated liposomal subjects who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF. In contrast, 10 of 48 doxorubicin subjects who had cardiac toxicity by LVEF criteria also developed signs and symptoms of CHF.

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-146370 · Präparat HOS-099502

In patients with solid tumours, including a subset of patients with breast and ovarian cancers, treated at a dose of 50 mg/m2/cycle with lifetime cumulative anthracycline doses up to 1,532 mg/m2, the incidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with doxorubicin pegylated liposomal 50 mg/m2/cycle, and having a baseline measurement of left ventricular ejection fraction (LVEF) and at least one follow-up measurement assessed by MUGA scan, 88 patients had a cumulative anthracycline dose of > 400 mg/m2, an exposure level associated with an increased risk of cardiovascular toxicity with conventional doxorubicin. Only 13 of these 88 patients (15%) had at least one clinically significant change in their LVEF, defined as an LVEF value less than 45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (cumulative

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Nebenwirkungen · Zolsketil pegylated liposomal

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15–16

HOS-146371 · Präparat HOS-099502

3 anthracycline dose of 944 mg/m2), discontinued study treatment because of clinical symptoms of congestive heart failure.

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